脑胰岛素抵抗与麻醉/手术引起的认知功能恶化的关联在 5XFAD 转基因小鼠中具有性别特异性。

The Association of Brain Insulin Resistance with Anesthesia/Surgery-Induced Cognitive Deterioration Is Female-Specific in 5XFAD Transgenic Mice.

机构信息

Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China.

出版信息

J Alzheimers Dis. 2024;101(1):183-195. doi: 10.3233/JAD-231444.

DOI:10.3233/JAD-231444

PMID:39213082

Abstract

BACKGROUND

Our previous studies indicated that anesthesia/surgery could aggravate cognitive impairment and tau pathology in female 5XFAD transgenic (Tg) mice. However, it is unknown whether there are sex differences in the susceptibility of developing postoperative cognitive dysfunction in 5XFAD Tg mice.

OBJECTIVE

In this study, we aim to determine whether anesthesia/surgery can have different effects on female and male 5XFAD Tg mice, and to explore the underpinning mechanisms.

METHODS

The mice received abdominal surgery under isoflurane anesthesia. Morris water maze was used to assess the cognitive function. Hippocampal levels of p-tau (AT8), p-IRS1 (Ser612), IRS1, p-GSK3β (Tyr216), and p-GSK3β (Ser9) at postoperative day 1 were evaluated by western blot assays.

RESULTS

Anesthesia/surgery exaggerated cognitive impairment and tau pathology in female, but not male 5XFAD Tg mice. The anesthesia/surgery led to elevated hippocampus protein levels of p-IRS1 (Ser612)/IRS1 ratio and p-GSK3β (Tyr216) and reduced hippocampus protein levels of p-GSK3β (Ser9) in female, but not male 5XFAD Tg mice.

CONCLUSIONS

This study demonstrated that female 5XFAD Tg mice were more susceptible to anesthesia/surgery-induced cognitive deterioration and tau pathology aggravation, potentially due to female-specific brain insulin resistance.

摘要

背景

我们之前的研究表明，麻醉/手术会加重雌性 5XFAD 转基因（Tg）小鼠的认知障碍和 tau 病理学。然而，目前尚不清楚 5XFAD Tg 小鼠在术后认知功能障碍的易感性方面是否存在性别差异。

目的

本研究旨在确定麻醉/手术是否对雌性和雄性 5XFAD Tg 小鼠有不同的影响，并探讨其潜在机制。

方法

小鼠接受异氟烷麻醉下的腹部手术。通过 Morris 水迷宫评估认知功能。Western blot 检测术后第 1 天海马体中 p-tau（AT8）、p-IRS1（Ser612）、IRS1、p-GSK3β（Tyr216）和 p-GSK3β（Ser9）的水平。

结果

麻醉/手术使雌性 5XFAD Tg 小鼠的认知障碍和 tau 病理学加重，而对雄性 5XFAD Tg 小鼠没有影响。麻醉/手术导致雌性 5XFAD Tg 小鼠海马体中 p-IRS1（Ser612）/IRS1 比值和 p-GSK3β（Tyr216）的蛋白水平升高，而 p-GSK3β（Ser9）的蛋白水平降低，但在雄性 5XFAD Tg 小鼠中没有这种变化。